The present invention relates to improved polymers and polymerization processes, and are particularly suitable for producing polymers for a variety of uses, including pharmaceuticals, medical devices, food packaging materials and the like. The improved polymers have reduced levels of contaminants as compared to the commercial polymers currently available, as demonstrated below, and thus are ideal for situations where the polymer, or compositions in contact with the polymer, are injected or inserted into, placed within or on, and/or ingested by a living organism. The ability to reduce contaminant levels according to the invention permits greater flexibility in terms of polymerization reaction conditions, including types and amount of catalysts and reactants, as well as expanding the fields of use for polymers and polymer preparations. See U.S. Ser. No. 60/228,729, the entirety of which is hereby incorporated by reference.
The present invention also relates to various polymers, which include the phosphopolymers, which are polymers containing phosphorous linkages. Phosphopolymers include the polyphosphoester polymers (xe2x80x9cpolyphosphoestersxe2x80x9d). These polymers are considered to be biodegradeable polymers having phosphorous-based linkages.
Polyphosphoesters contain phosphate ester bonds, phosphonate ester bonds and/or phosphite ester bonds. Certain polyphosphoesters have hydrolyzable bonds, and as such are considered useful in in vivo contexts because they are biodegradable/biocompatiblexe2x80x94at least in part by virtue of the labile phosphoester bond in the polymer backbone. New and useful biodegradable phosphopolymers have previously been produced. See U.S. Pat. Nos. 5,952,451 and 6,008,318; and PCT publications WO 98/44020, WO 98/44021, and WO 98/48859, which are hereby incorporated by reference in their entirety.
Polyphosphoesters have been produced using bulk melt polymerization processes, such as polymerizations using L-lactide, ethylene glycol and ethyl phosphorodichloridate: 
This example is Poly(L-lactide-co-ethyl phosphate), referred to as Poly(LA-EG-EOP).
Similar approaches have been used to form Poly(L-lactide-co-hexyl phosphate), referred to as Poly(LAEG-HOP), except that hexyl phosphodichloridate (HOP) substitutes for ethyl phosphorodichloridate (EOP). The polymer is depicted below: 
Many previous production methodologies have been comparatively energy and time consuming in terms of overall yield. Accordingly, there is a desire to improve production methodologies to provide greater efficiency and control over the polymerization process. The invention disclosed herein provides improved production methodologies, which result in more efficient production, enhanced purity, better polymer properties, increased yields and improved control over molecular weight and other properties.
For convenience, before further description of the present invention, certain terms employed in the specification, examples, and appended claims are collected and explained here. These definitions should be read in light of the remainder of the disclosure and understood as by a person of skill in the art.
The terms xe2x80x9cbiocompatible polymerxe2x80x9d and xe2x80x9cbiocompatibility,xe2x80x9d in their various grammatical forms, when used in relation to polymers are art-recognized. For example, biocompatible polymers include polymers that are neither themselves toxic to the host (e.g., an animal or human), nor degrade (if the polymer degrades) at a rate that produces monomeric or oligomeric subunits or other byproducts at toxic concentrations in the host. In certain embodiments of the present invention, biodegradation generally involves degradation of the polymer in an organism, e.g., into its monomeric subunits, which may be known to be effectively non-toxic. Intermediate oligomeric products resulting from such degradation may have different toxicological properties in some instances, however, or biodegradation may involve oxidation or other biochemical reactions that generate molecules other than monomeric subunits of the polymer. Consequently, it may be desired in some circumstances to evaluate the toxicology of a biodegradable polymer intended for in vivo use, such as implantation or injection into a patient, which may be readily determined after one or more toxicity analyses. It is not necessary that any subject composition have a purity of 100% to be deemed biocompatible; indeed, it is only necessary that the subject compositions be biocompatible as set forth above. Hence, a subject composition may comprise a polymer comprising 99%, 98%, 97%, 96%, 95%, 90%, 85%, 80%, 75% or even less of biocompatible polymers, e.g., including polymers and other materials and excipients described herein, and still be biocompatible.
As mentioned above, to determine whether a polymer or other material is biocompatible, it may be desirable to conduct a toxicity analysis. Such assays are well known in the art, and are performed routinely. One example of such an assay may be performed with live carcinoma cells, such as GT3TKB tumor cells, in the following manner: the sample is degraded in 1M NaOH at 37xc2x0 C. until complete degradation is observed. The solution is then neutralized with 1M HCl. About 200 xcexcL of various concentrations of the degraded sample products are placed in 96-well tissue culture plates and seeded with human gastric carcinoma cells (GT3TKB) at 104/well density. The degraded sample products are incubated with the GT3TKB cells for 48 hours. The results of the assay may be plotted as % relative growth vs. concentration of degraded sample in the tissue-culture well. In addition, polymers and formulations of the present invention may also be evaluated by well-known in vivo tests, such as subcutaneous implantations in rats to confirm that they hydrolyze without significant levels of irritation or inflammation at the subcutaneous implantation sites.
In certain embodiments, polymeric formulations of the present invention biodegrade within a period that is acceptable in the desired application. In certain embodiments, such as in vivo therapy, such degradation occurs in a period usually less than about five years, one year, six months, three months, one month, fifteen days, five days, three days, or even one day on exposure to a physiological solution with a pH between 6 and 8 having a temperature of between 25 and 37xc2x0 C. In other embodiments, the polymer degrades in a period of between about one hour and several weeks, depending on the desired application.
The term xe2x80x9cbiodegradable,xe2x80x9d in its various grammatical forms, is art-recognized, and includes polymers, compositions and formulations, such as those described herein, that are intended to degrade during use. Biodegradable polymers typically differ from non-biodegradable polymers in that the former may be degraded during use. In certain embodiments, such use involves in vivo use, such as in vivo therapy, and in other certain embodiments, such use involves in vitro use. In general, degradation attributable to biodegradability involves the degradation of a biodegradable polymer into its component subunits, or digestion, e.g., by a biochemical process, of the polymer into smaller, non-polymeric subunits. In certain embodiments, two different types of biodegradation may generally be identified. For example, one type of biodegradation may involve cleavage of bonds (whether covalent or otherwise) in the polymer backbone. In such biodegradation, monomers and oligomers typically result, and even more typically, such biodegradation occurs by cleavage of a bond connecting one or more of subunits of a polymer. In contrast, another type of biodegradation may involve cleavage of a bond (whether covalent or otherwise) internal to side chain or that connects a side chain to the polymer backbone. For example, a therapeutic agent or other chemical moiety attached as a side chain to the polymer backbone may be released by biodegradation. In certain embodiments, one or the other or both generally types of biodegradation may occur during use of a polymer. As used herein, the term xe2x80x9cbiodegradationxe2x80x9d encompasses both general types of biodegradation.
The degradation rate of a biodegradable polymer often depends in part on a variety of factors, including the chemical identity of the linkage responsible for any degradation, the molecular weight, crystallinity, biostability, and degree of cross-linking of such polymer, the physical characteristics of the implant, shape and size, and the mode and location of administration. For example, the greater the molecular weight, the higher the degree of crystallinity, and/or the greater the biostability, the biodegradation of any biodegradable polymer is usually slower. The term xe2x80x9cbiodegradablexe2x80x9d is intended to cover materials and processes also termed xe2x80x9cbioerodiblexe2x80x9d.
In certain embodiments, if the biodegradable polymer also has a therapeutic agent or other material associated with it, the biodegradation rate of such polymer may be characterized by a release rate of such materials. In such circumstances, the biodegradation rate may depend on not only the chemical identity and physical characteristics of the polymer, but also on the identity of any such material incorporated therein.
A variety of polymers may be used in the subject invention. Both non-biodegradable and biodegradable polymers may be used in the subject invention, although biodegradable polymers in certain contexts are preferred. As discussed below, the choice of polymer will depend in part on a variety of physical and chemical characteristics of such polymer and the use to which such polymer may be put.
In certain embodiments, polymers having phosphorus linkages may be used in the subject invention. Exemplary phosphorus linkages in such polymers include, without limitation, phosphonamidite, phosphoramidite, phosphorodiamidate, phosphomonoester, phosphodiester, phosphotriester, phosphonate, phosphonate ester, phosphorothioate, thiophosphate ester, phosphinate or phosphite. Any of the subject polymers may be provided as copolymers, terpolymers, etc. Certain of such polymers may be biodegradable, biocompatible or both.
The structure of certain of the foregoing polymers having phosphorus linkages may be identified as follows. The term xe2x80x9cbiodegradable polymer having phosphorous-based linkagesxe2x80x9d is used herein to refer to polymers in which the following substructure is present at least a multiplicity of times in the backbone of such polymer: 
wherein, independently for each occurrence of such substructure:
X1, each independently, represents xe2x80x94Oxe2x80x94 or xe2x80x94N(R5)xe2x80x94;
R5 represents xe2x80x94H, aryl, alkenyl or alkyl; and
R6 is any non-interfering substituent,
wherein such substructure is responsible in part for biodegradability properties observed for such polymer in vitro or in vivo. In certain embodiments, R6 may represent an alkyl, aralkyl, alkoxy, alkylthio, or alkylamino group.
In certain embodiments, such a biodegradable polymer is non-naturally occurring, i.e., a man-made product with no natural source. In other embodiments, R6 is not xe2x80x94OH or halogen, e.g., is an alkyl, aralkyl, aryl, alkoxyl, aryloxy, or aralkyloxy. In still other embodiments, the two X1 moieties in such substructure are the same. For general guidance, when reference is made to the xe2x80x9cpolymer backbone chainxe2x80x9d or the like of a polymer, with reference to the above structure, such polymer backbone chain comprises the motif [xe2x80x94X1xe2x80x94Pxe2x80x94X1xe2x80x94]. In other polymers, the polymer backbone chain may vary as recognized by one of skill in the art.
By way of example, but not limitation, a number of representative polymers having phosphorus linkages are described in greater detail below. In certain embodiments, a polymer includes one or more monomeric units of Formula II: 
wherein, independently for each occurrence of such unit:
X1, each independently, represents xe2x80x94Oxe2x80x94 or xe2x80x94N(R7)xe2x80x94;
R7 represents xe2x80x94H, aryl, alkenyl or alkyl;
L1 is described below;
R8 represents, for example, xe2x80x94H, alkyl, xe2x80x94O-alkyl, xe2x80x94O-cycloalkyl, aryl, xe2x80x94O-aryl, heterocycle, xe2x80x94O-heterocycle, xe2x80x94Cl, xe2x80x94N(R9)R10 and other examples presented below;
R9 and R10, each independently, represent a hydrogen, an alkyl, an alkenyl, xe2x80x94(CH2)n-R11, or R9 and R10, taken together with the N atom to which they are attached complete a heterocycle having from 4 to about 8 atoms in the ring structure; and
R11 represents xe2x80x94H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle or polycycle.
L1 may be any chemical moiety as long as it does not materially interfere with the polymerization or biodegradation (or both) of the polymer, wherein a xe2x80x9cmaterial interferencexe2x80x9d or xe2x80x9cnon-interfering substituentxe2x80x9d is understood to mean, for synthesis of the polymer by polymerization, an inability to prepare the subject polymer by methods known in the art or taught herein, and for biodegradation, a reduction in the biodegradation of the subject polymer so as to make such polymer impracticable for biodegradation.
In certain embodiments, L1 is an organic moiety, such as a divalent branched or straight chain or cyclic aliphatic group or divalent aryl group, with in certain embodiments, from 1 to about 20 carbon atoms. In certain embodiments, L1 represents a moiety between about 2 and 20 atoms selected from carbon, oxygen, sulfur, and nitrogen, wherein at least 60% of the atoms are carbon. In certain embodiments, L1 may be an alkylene group, such as methylene, ethylene, 1,2-dimethylethylene, n-propylene, isopropylene, 2,2-dimethylpropylene, n-pentylene, n-hexylene, n-heptylene; an alkenylene group such as ethenylene, propenylene, 2-(3-propenyl)-dodecylene; and an alkynylene group such as ethynylene, proynylene, 1-(4-butynyl)-3-methyldecylene; and the like. Such unsaturated aliphatic groups may be used to cross-link certain embodiments of the present invention.
Further, L1 may be a cycloaliphatic group, such as cyclopentylene, 2-methylcyclopentylene, cyclohexylene, cyclohexylenedimethylene, cyclohexenylene and the like. L1 may also be a divalent aryl group, such as phenylene, benzylene, naphthalene, phenanthrenylene and the like. Further, L1 may be a divalent heterocyclic group, such as pyrrolylene, furanylene, thiophenylene, alkylyene-pyrrolylene-alkylene, pyridinylene, pyrimidinylene and the like.
Other examples of L1 may include any of the polymers listed above, including the biodegradable polymers listed above, and in particular polylactide, polyglycolide, polycaprolactone, polycarbonate, polyethylene terephthalate, polyanhydride and polyorthoester, and polymers of ethylene glycol, propylene glycol and the like. Embodiments containing such polymers for L1 may impart a variety of desired physical and chemical properties.
The foregoing, as with other moieties described herein, may be substituted with a non-interfering substituent, for example, a hydroxy-, halogen-, or nitrogen-substituted moiety.
R8 represents hydrogen, alkyl, cycloakyl, xe2x80x94O-alkyl, xe2x80x94O-cycloalkyl, aryl, xe2x80x94O-aryl, heterocycle, xe2x80x94O-heterocycle, or xe2x80x94N(R9)R10. Examples of possible alkyl R8 groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, xe2x80x94C8H17 and the like groups; and alkyl substituted with a non-interfering substituent, such as hydroxy, halogen, alkoxy or nitro; corresponding alkoxy groups.
When R8 is aryl or the corresponding aryloxy group, it typically contains from about 5 to about 14 carbon atoms, or about 5 to about 12 carbon atoms, and optionally, may contain one or more rings that are fused to each other. Examples of particularly suitable aromatic groups include phenyl, phenoxy, naphthyl, anthracenyl, phenanthrenyl and the like.
When R8 is heterocyclic or heterocycloxy, it typically contains from about 5 to about 14 ring atoms, alternatively from about 5 to about 12 ring atoms, and one or more heteroatoms. Examples of suitable heterocyclic groups include furan, thiophene, pyrrole, isopyrrole, 3-isopyrrole, pyrazole, 2-isoimidazole, 1,2,3-triazole, 1,2,4-triazole, oxazole, thiazole, isothiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3,4-oxatriazole, 1,2,3,5-oxatriazole, 1,2,3-dioxazole, 1,2,4-dioxazole, 1,3,2-dioxazole, 1,3,4-dioxazole, 1,2,5-oxatriazole, 1,2-pyran, 1,4-pyran, 1,2-pyrone, 1,4-pyrone, 1,2-dioxin, 1,3-dioxin, pyridine, N-alkyl pyridinium, pyridazine, pyrimidine, pyrazine, 1,3,5-triazine, 1,2,4-triazine, 1,2,3-triazine, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, o-isoxazine, p-isoxazine, 1,2,5-oxathiazine, 1,2,6-oxathiazine, 1,4,2-oxadiazine, 1,3,5-oxadiazine, azepine, oxepin, thiepin, indene, isoindene, benzofuran, isobenzofuran, thionaphthene, isothionaphthene, indole, indolenine, 2-isobenzazole, isoindazole, indoxazine, benzoxazole, anthranil, 1,2-benzopyran, 1,2-benzopyrone, 1,4-benzopyrone, 2,1-benzopyrone, 2,3-benzopyrone, quinoline, isoquinoline, 12,-benzodiazine, 1,3-benzodiazine, naphthyridine, pyrido-[3,4-b]-pyridine, pyrido-[3,2-b]-pyridine, pyrido-[4,3-b]-pyridine, 1,3,2-benzoxazine, 1,4,2-benzoxazine, 2,3,1-benzoxazine, 3,1,4-benzoxazine, 1,2-benzisoxazine, 1,4-benzisoxazine, carbazole, xanthrene, acridine, purine, and the like. In certain embodiments, when R8 is heterocyclic or heterocycloxy, it is selected from the group consisting of furan, pyridine, N-alkylpyridine, 1,2,3- and 1,2,4-triazoles, indene, anthracene and purine rings.
In certain embodiments, R8 is an alkyl group, an alkoxy group, a phenyl group, a phenoxy group, a heterocycloxy group, or an ethoxy group.
In still other embodiments, R8, such as an alkyl, may be conjugated to a bioactive substance to form a pendant drug delivery system.
In certain embodiments, the number n in Formula II and other subject formulas ranges over a wide range, e.g., from about 5 to 25,000 or more, but generally from about 100 to 5000, or 10,000. Alternatively, in other embodiments, n may be about 10, 25, 50, 75, 100, 150, 200, 300 or 400.
In Formula II and other formulas herein, xe2x80x9c*xe2x80x9d represents other monomeric units of the subject polymer, which may be the same or different from the unit depicted in the formula in question, or a chain terminating group, by which the polymer terminates. Examples of such chain terminating groups include monofunctional alcohols and amines.
In another aspect, the polymeric compositions of the present invention include one or more recurring monomeric units represented in general Formula III: 
wherein Z1 and Z2, respectively, for each independent occurrence is: 
wherein, independently for each occurrence set forth above:
Q1, Q2 . . . Qs, each independently, represent O or N(R1);
X1, X2 . . . Xs, each independently, represent xe2x80x94Oxe2x80x94 or xe2x80x94N(R1);
the sum of t1, t2 . . . ts is an integer and at least one or more;
Y1 represents xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94N(R7)xe2x80x94;
x and y are each independently integers from 1 to about 1000 or more;
L1 and M1, M2 . . . Ms each independently, represent the moieties discussed below; and
the other moieties are as defined above.
M1, M2 . . . Ms (collectively, M) in Formula III are each independently any chemical moiety as long as it does not materially interfere with the polymerization or biodegradation (or both) of the polymer. For certain embodiments, M in the formula are each independently: (i) a branched or straight chain aliphatic or aryl group having from 1 to about 50 carbon atoms, or (ii) a branched or straight chain, oxa-, thia-, or aza-aliphatic group having from 1 to about 50 carbon atoms. In certain embodiments, the number of such carbon atoms does not exceed 20. In other embodiments, M may be any divalent aliphatic moiety having from 1 to about 20 carbon atoms, including therein from 1 to about 7 carbon atoms, that does not cause any material interference with the polymerization or biodegradation (or both) of the subject polymer.
M may include an aromatic or heteroaromatic moiety, optionally with non-interfering substituents. In certain embodiments, none of the atoms (usually but not always C) that form the cyclic ring that gives rise to the aromatic moiety are part of the polymer backbone chain.
Specifically, when M is a branched or straight chain aliphatic group having from 1 to about 20 carbon atoms, it may be, for example, an alkylene group such as methylene, ethylene, 1-methylethylene, 1,2-dimethylethylene, n-propylene, trimethylene, isopropylene, 2,2-dimethylpropylene, n-pentylene, n-hexylene, n-heptylene, n-octylene, n-nonylene, n-decylene, n-undecylene, n-dodecylene, and the like; an alkenylene group such as n-propenylene, 2-vinylpropylene, n-butenylene, 3-thexylbutylene, n-pentenylene, 4-(3-propenyl)hexylene, n-octenylene, 1-(4-butenyl)-3-methyldecylene, 2-(3-propenyl)dodecylene, hexadecenylene and the like; an alkynylene group, such as ethynylene, propynylene, 3-(2-ethynyl)pentylene, n-hexynylene, 2-(2-propynyl)decylene, and the like; or any alkylene, alkenylene or alkynylene group, including those listed above, substituted with a materially non-interfering substituent, for example, a hydroxy, halogen or nitrogen group, such as 2-chloro-n-decylene, 1-hydroxy-3-ethenylbutylene, 2-propyl-6-nitro-10-dodecynylene, and the like. Other M of the present invention include xe2x80x94(CH2)3xe2x80x94, xe2x80x94(CH2)5xe2x80x94 and (CH2)2OOCH2xe2x80x94.
When M is a branched or straight chain oxaaliphatic group having from 1 to about 20 carbon atoms, it may be, for example, a divalent alkoxylene group, such as ethoxylene, 2-methylethoxylene, propoxylene, butoxylene, pentoxylene, dodecyloxylene, hexadecyloxylene, and the like. When M is a branched or straight chain oxaaliphatic group, it may have the formula xe2x80x94(CH2)axe2x80x94Oxe2x80x94(CH2)bxe2x80x94 wherein each of a and b, independently, is about 1 to about 7.
When M is a branched or straight chain oxaaliphatic group having from 1 to about 20 carbon atoms, it may also be, for example, a dioxaalkylene group such as dioxymethylene, dioxyethylene, 1,3-dioxypropylene, 2-methoxy-1,3-dioxypropylene, 1,3-dioxy-2-methylpropylene, dioxy-n-pentylene, dioxy-n-octadecylene, methoxylene-methoxylene, ethoxylene-methoxylene, ethoxylene-ethoxylene, ethoxylene-1-propoxylene, butoxylene-n-propoxylene, pentadecyloxylene-methoxylene, and the like. When M is a branched or straight chain, dioxyaliphatic group, it may have the formula xe2x80x94(CH2)axe2x80x94Oxe2x80x94(CH2)bxe2x80x94Oxe2x80x94(CH2)cxe2x80x94, wherein each of a, b, and c is independently from 1 to about 7.
When M is a branched or straight chain thiaaliphatic group, the group may be any of the preceding oxaaliphatic groups wherein the oxygen atoms are replaced by sulfur atoms.
When M is a branched or straight chain, aza-aliphatic group having from 1 to about 20 carbon atoms, it may be a divalent group such as xe2x80x94CH2NHCH2xe2x80x94, xe2x80x94(CH2)2NCH2xe2x80x94, xe2x80x94CH2(C2H5)NCH2CH2xe2x80x94, -n-C4H9NHCH2xe2x80x94, -t-C4H9NHCH2CH2xe2x80x94, xe2x80x94CH2(C3H7)N(CH2)4xe2x80x94, xe2x80x94C2H5(C2H5)NCH2xe2x80x94, xe2x80x94CH2(C8H17)NCH2CH2xe2x80x94, and the like. When M is a branched or straight chain, amino-aliphatic group, it may have the formula xe2x80x94(CH2)aN(R1)(CH2)bxe2x80x94 where R1 is xe2x80x94H, aryl, alkenyl or alkyl and each of a and b is independently from about 1 to about 7.
x and y of Formula III each independently represent integers in the range of about 1 to about 1000, e.g., about 1, about 10, about 20, about 50, about 100, about 250, about 500, about 750, about 1000, etc.
The molar ratio of n:(x or y) in Formula III may vary greatly, typically between about 200:1 and 1:200. In certain embodiments, the ratio n:(x or y) is from about 100:1 to about 1:100, from about 50:1 to about 1:50, and alternatively, from about 25:1 to about 1:25. In certain embodiments, the ratio of n:x to n:y need not be the same. The molar ratio of x:y may also vary; typically, such ratio is about 1. Other possible embodiments may have ratios of 0.1, 0.25, 0.5, 0.75, 1.5, 2, 3, 4, 10 and the like.
A number of different polymer structures are contemplated by Formula III. For example, in certain polymers exemplified by Formula III, when the sum of t1, t2 . . . ts equals one for each of Z1 and Z2 and Q, M and X for each subunit ts are the same, then Formula III becomes the following Formula IIIa: 
In certain embodiments of Formula IIIa (and other subject formulas), x and y may be even integers.
The above Formula III (and all of the subject formulae and polymers) encompass a variety of different polymer structures, including block copolymers, random copolymers, random terpolymers and segmented block copolymers and terpolymers. Additional structures for Z of subject monomeric units are set forth below, which exemplify in part the variety of structures contemplated by the present invention: 
In Formula IIIb (and other formulas described below), there may be more ts subunits depicted of the same molecular identity of those depicted in the formulas. For example, in Formula IIIb, subunits t1 and t2 may be repeated in a sequence, e.g., alternating, in blocks (which may themselves repeat), or in any other pattern or random arrangement. Each subunit may repeat any number of times, and one subunit (e.g., t1) may occur with substantially the same frequency, more often, or less often than another subunit (e.g., t2), such that both subunits may be present in approximately the same amount, or in differing amounts, which may differ slightly or be highly disparate, e.g., one subunit is present nearly to the exclusion of the other. In certain embodiments, the chiral centers of each subunit may be the same or different and may be arranged in an orderly fashion or in a random sequence in each of Z1 and Z2. 
In certain embodiments of Formula IIIc, the sum of the number of ts subunits in each of Z1 and Z2 is an even integer. As in other examples of Z1 and Z2, such as described above for Formula III, the ts subunits may be distributed randomly or in an ordered arrangement in each of Z1 or Z2. 
In Formula IIId, the subunit q1 is comprised of two ts subunits, which may be repeated and arranged as described above for Formula IIIb. In certain embodiments, q2 is an even integer, and in other embodiments, the subunits q1 and q2 may be distributed randomly or in an ordered pattern in each of Z1 and Z2. For example, subunits q1 and q2 may be repeated in a sequence, e.g., alternating, in blocks (which may themselves repeat), or in any other pattern or random arrangement. Each subunit may repeat any number of times, and one subunit (e.g., ql) may occur with substantially the same frequency, more often, or less often than another subunit (e.g., q2), such that both subunits may be present in approximately the same amount, or in differing amounts, which may differ slightly or be highly disparate, e.g., one subunit is present nearly to the exclusion of the other. 
In certain embodiments of Formula IIIe, the sum of the ts subunits for each of Z1 and Z2 is an even integer. In other embodiments, the each of the subunits t1, t2, and t3 may be distributed randomly or in an ordered arrangement in each of Z1 and Z2. For example, in Formula IIIe, subunits t1, t2, and t3 may be repeated in a sequence, e.g., alternating, in blocks (which may themselves repeat), or in any other pattern or random arrangement. Each subunit may repeat any number of times, and one subunit (e.g., t1) may occur with substantially the same frequency, more often, or less often than another subunit (e.g., t3), such that the three subunits may be present in approximately the same amount, or in differing amounts, which may differ slightly or be highly disparate, e.g., two subunits are present nearly to the exclusion of the third.
In certain embodiments of Formula III, in which Q, M and X for each subunit are the same, Q1 represents 0, M represents a lower alkylene group, and X1 represents O or S, preferably O. For example, M may represent xe2x80x94CH(CH3)xe2x80x94 to result in a polymer of Formula III having a structure represented in Formula III; 
In certain embodiments of Formula IIIf, as further described in the Exemplification below, L1 represents a lower alkylene chain, such as ethylene, propylene, etc. In certain embodiments, all Y1""s represent O. In certain embodiments, R8 represents xe2x80x94O-lower alkyl, such as xe2x80x94OEt.
In certain embodiments of polymers depicted by Formula III, the chirality of each subunit is identical, whereas in other embodiments, the chirality is different. By way of example but not limitation, in Formula IIIb above, if the chiral centers of all of the subunits are D-enantiomers or L-enantiomers, then the monomeric unit is effectively equivalent to D-lactic acid or L-lactic acid, respectively, thereby giving rise to a region similar to poly(D-lactic acid) or poly-(L-lactic acid), respectively. Conversely, if the two subunits in Formula IIIb are comprised of alternating D- and L-enantiomers (e.g., one unit of D-enantiomer, one unit of L-enantiomer, etc.), then the resulting polymeric region is analogous to poly(meso-lactic acid) (i.e., a polymer formed by polymerization of meso-lactide).
Finally, in certain embodiments of the monomeric units set forth in Formula III, in which the entire polymer may or may not be composed of such units, the following moieties for Y1, L1, R8 Qs, Xs and Ms may be used (with a variety of different x and y being possible):
In addition to the particular chiral version of the subject polymers described in the above table, polymers in which the chirality of Ms varies in each subunit M in the subject polymers are also possible. For instance, referring to P(D,L-A-EG-EOP) by example, a random order of D and L, in varying amounts, are possible for this polymer. In contrast, the table sets forth one such example in which a D and L chiral M are always adjacent, in equal amounts, but that need not always be the case.
In another embodiment of the present invention, the polymeric compositions of the present invention include one or more recurring monomeric units represented in general Formula IV: 
wherein, independently for each occurrence:
L2 is a divalent organic group as described in greater detail below; and
the other moieties are as defined as above.
In Formula IV, L2 may be a divalent, branched or straight chain aliphatic group, a cycloaliphatic group, or a group of the formula: 
Specific examples of particular divalent, branched or straight chain aliphatic groups include an alkylene group with 1 to 7 carbon atoms, such as 2-methylpropylene or ethylene. Specific examples of cycloaliphatic groups include cycloalkylene groups, such as cyclopentylene, 2-methylcyclopentylene, cyclohexylene and 2-chioro-cyclohexylene; cycloalkenylene groups, such as cyclohexenylene; and cycloalkylene groups having fused or bridged additional ring structures, such as tetralinylene, decalinylene and norpinanylene; or the like.
In certain embodiments of the subject formulas, each of L1 independently may be an alkylene group, a divalent cycloaliphatic group, a phenylene group or a divalent group of the formula: 
wherein D is O, N or S and m is 0 to 3. Alternatively, L1 is a branched or straight chain alkylene group having from 1 to 7 carbon atoms, such as a methylene, ethylene, n-propylene, 2-methylpropylene, 2,2xe2x80x2-dimethylpropylene group and the like.
In certain embodiments of the monomeric units set forth in Formula IV, in which the entire polymer may or may not be composed of such units, the following moieties for X1, L1 and R8 may be used:
In another embodiment of the present invention, the polymeric compositions of the present invention include one or more recurring monomeric units represented in general Formula V: 
wherein, independently for each occurrence, d is equal to one or more, and optionally two, and all of the other moieties are as defined above.
In certain embodiments of the monomeric units set forth in Formula V, in which the entire polymer may or may not be composed of such units, the following moieties for X1, L1 and R8 may be used (with a variety of different x possible for each example):
In Formula V, the aryl groups represented therein may be substituted with a non-interfering substituent, for example, a hydroxy-, halogen-, or nitrogen-substituted moiety.
Other phosphorus-containing polymers which may be adapted for use in the subject invention are described in the art, including those described in U.S. Pat. Nos. 5,256,765 and 5,194,581; PCT publications WO 98/44020, WO 98/44021, and WO 98/48859; and U.S. application Ser. Nos. 09/053,649, 09/053,648 and 09/070,204. For all of the above-identified groups, non-interfering substituents also may be present.
In certain embodiments, the polymers are comprised almost entirely, if not entirely, of the same subunit. Alternatively, in other embodiments, the polymers may be copolymers, in which different subunits and/or other monomeric units are incorporated into the polymer. In certain instances, the polymers are random copolymers, in which the different subunits and/or other monomeric units are distributed randomly throughout the polymer chain. For example, a polymer having units of Formula II may consist of effectively only one type of such subunit, or alternatively two or more types of such subunits. In addition, a polymer may contain monomeric units other than those subunits represented by Formula II.
In other embodiments, the different types of monomeric units, be they one or more subunits depicted by the subject formulas or other monomeric units, are distributed randomly throughout the chain. In part, the term xe2x80x9crandomxe2x80x9d is intended to refer to the situation in which the particular distribution or incorporation of monomeric units in a polymer that has more than one type of monomeric units is not directed or controlled directly by the synthetic protocol, but instead results from features inherent to the polymer system, such as the reactivity, amounts of subunits and other characteristics of the synthetic reaction or other methods of manufacture, processing or treatment.
In certain embodiments, the subject polymers may be cross-linked. For example, substituents of the polymeric chain, may be selected to permit additional inter-chain cross-linking by covalent or electrostatic (including hydrogen-binding or the formation of salt bridges), e.g., by the use of a organic residue appropriately substituted.
The ratio of different subunits in any polymer as described above may vary. For example, in certain embodiments, polymers may be composed almost entirely, if not entirely, of a single monomeric element, such as a subunit depicted in Formula II. Alternatively, in other instances, the polymers are effectively composed of two different subunits, in which the percentage of each subunit may vary from less than 1:99 to more than 99:1, or alternatively 10:90, 15:85, 25:75, 40:60, 50:50, 60:40, 75:25, 85:15, 90:10 or the like. For example, in some instances, a polymer may be composed of two different subunits that may be both represented by the generic Formula II, for example, but which differ in their chemical identity. In certain embodiments, the polymers may have just a few percent, or even less (for example, about 5, 2.5, 1, 0.5, 0.1%) of the subunits having phosphorous-based linkages. In other embodiments, in which three or more different monomeric units are present, the present invention contemplates a range of mixtures like those taught for the two-component systems.
In certain embodiments, the polymeric chains of the subject compositions, e.g., which include repetitive elements shown in any of the subject formulas, have molecular weights ranging from about 2000 or less to about 1,000,000 or more daltons, or alternatively about 10,000, 20,000, 30,000, 40,000, or 50,000 daltons, more particularly at least about 100,000 daltons, and even more specifically at least about 250,000 daltons or even at least 500,000 daltons. Number-average molecular weight (Mn) may also vary widely, but generally fall in the range of about 1,000 to about 200,000 daltons, preferably from about 1,000 to about 100,000 daltons and, even more preferably, from about 1,000 to about 50,000 daltons. Most preferably, Mn varies between about 8,000 and 45,000 daltons. Within a given sample of a subject polymer, a wide range of molecular weights may be present. For example, molecules within the sample may have molecular weights which differ by a factor of 2, 5, 10, 20, 50, 100, or more, or which differ from the average molecular weight by a factor of 2, 5, 10, 20, 50, 100, or more.
One method to determine molecular weight, both number average and weight average, is by gel permeation chromatography (xe2x80x9cGPCxe2x80x9d), e.g., through the use of mixed bed columns, CH2Cl2 solvent, light scattering detector, and off-line dn/dc. Polymer Laboratories and Waters. Laser light scattering devices are available from Wyatt Laboratories.
Exemplary approaches are as follows: weight-Average MWs from light scattering, Mw (LS), can be obtained using a system incorporating a Waters 510 pump, two Polymer Labs xe2x80x9cMixed Cxe2x80x9d columns in series, a Shimadzu CTO-10A column oven, a Waters 410 differential refractometer, and a MiniDawn multi-angle light scattering detector (Wyatt Technologies). Data can be obtained and analyzed on a PC using Astra software (Wyatt Technologies). Weight-Average MWs and Number-Average MWs from conventional calibration, Mw (CC) and Mn (CC) can be obtained using the system described above through the Waters 410 differential refractometer using a Polymer Labs data capture unit and Caliber software. A calibration curves can be obtained using Polymer Laboratories Easi-Cal PS-1 polystyrene standards. Data typically are reported in daltons. Inherent Viscosities (IV) can be obtained using polymer solutions of 0.45 to 0.55% w/v in a Canon-Fenske viscometer, size 25, at 30xc2x0 C. Such data typically are reported in dL/g. Other methods are known in the art.
In certain embodiments, the intrinsic viscosities of the polymers generally vary from about 0.01 to about 2.0 dL/g in chloroform at 40xc2x0 C., alternatively from about 0.01 to about 1.0 dL/g and, occasionally, from about 0.01 to about 0.5 dL/g.
The glass transition temperature (Tg) of the subject polymers may vary widely, and depend on a variety of factors, such as the degree of branching in the polymer components, the relative proportion of phosphorous-containing monomer used to make the polymer, and the like. When the article of the invention is a rigid solid, the Tg is often within the range of from about xe2x88x9210xc2x0 C. to about 80xc2x0 C., particularly between about 0 and 50xc2x0 C. and, even more particularly between about 25xc2x0 C. to about 35xc2x0 C. In other embodiments, the Tg is preferably low enough to keep the composition of the invention flowable at body temperature. Then, the glass transition temperature of the polymer used in the invention is usually about 0 to about 37xc2x0 C., or alternatively from about 0 to about 25xc2x0 C.
In certain embodiments, substituents of the phosphorus atom, such as R8 in the above formulas, and other components of the subject polymers may permit additional inter-chain cross-linking by covalent or electrostatic interactions (including, for example, hydrogen-binding or the formation of salt bridges) by having a side chain of either of them appropriately substituted as discussed in greater detail below.
In other embodiments, the polymer composition of the invention may be a flexible or flowable material. By xe2x80x9cflowablexe2x80x9d is meant the ability to assume, over time, the shape of the space containing it at body temperature. This includes, for example, liquid compositions that are capable of being sprayed into a site; injected with a manually operated syringe fitted with, for example, a 23-gauge needle; or delivered through a catheter.
Also included by the term xe2x80x9cflowablexe2x80x9d, are highly viscous, xe2x80x9cgel-likexe2x80x9d materials at room temperature that may be delivered to the desired site by pouring, squeezing from a tube, or being injected with any one of the commercially available power injection devices that provide injection pressures greater than would be exerted by manual means alone for highly viscous, but still flowable, materials. When the polymer used is itself flowable, the polymer composition of the invention, even when viscous, need not include a biocompatible solvent to be flowable, although trace or residual amounts of biocompatible solvents may still be present.
In certain embodiments, the subject polymers are soluble in one or more common organic solvents for ease of fabrication and processing. Common organic solvents include such solvents as chloroform, dichloromethane, dichloroethane, 2-butanone, butyl acetate, ethyl butyrate, acetone, ethyl acetate, dimethylacetamide, N-methyl pyrrolidone, dimethylformamide, and dimethylsulfoxide.
The following chart provides an explanation of some of the more frequently employed abbreviations in this application:
In view of the above definitions and explanations, the present invention provides methods for producing polymers, such as phosphopolymers (e.g., polyphosphoesters), and polymers, such as phosphopolymers (e.g., polyphosphoesters), made by such methods.
The present invention also provides methods of purifying a polymer preparation. In accordance with one aspect of the invention, purification methods comprising contacting the polymer preparation with at least one ion exchange resin are provided. Polymer preparations refer to a mass, collection, concentration or aggregation of polymers, and can be in a solid form or in solution. In purifying, the preparation can be contacted with an acidic resin and a basic resin, such as a strong acidic resin and a weak basic resin. The ion exchange resins can remove a variety of contaminants from a polymer preparation, such as amines from the reaction and metal contaminants arising from polymerization catalysts like tin and zinc. Polymer preparations having a reduced level of metal contaminants that are obtainable by these methodologies also are provided. The polymer preparations can comprise phosphopolymers, including polyphosphoesters.
In accordance with another aspect of the invention, methods of producing a phosphopolymer, comprising reacting a reactive prepolymer, preferably dissolved in an appropriate solvent with an organophosphorous compound in the presence of at least one acid scavenger, preferably until substantially all of the organophosphorous compound has bound with the prepolymer to form a phosphopolymer; and purifying the phosphopolymer. A reactive prepolymer should have one or more, preferably at least two, reactive end groups. The reactive end groups include, but are not limited to, primary and secondary alcohol, amine, and thiol groups.
The reaction can be stopped/quenched with an alcohol prior to the purification. The reaction can performed at a warm temperature or a cold temperature. The purification preferably employs at least one ion exchange resin. The prepolymer can be formed from one or more monomers selected from the group consisting of D,L-lactide, trimethylene chloride, L-lactide, caproloactone, dioxanone, propylene glycol, ethylene glycol, 1,6 hexanediol, glycolide, 1,4-cyclohexane dimethanol, terephthaloyl chloride and bis(hydroxyethyl) terephthalate, for example. The organophosphorous compound can be selected from the group consisting of alkyl dichlorophosphates, alkyl dichlorophosphonates, alkyl dichlorophosphites, aryl dichlorophosphates, aryl dichlorophosphonates, aryl dichlorophosphites, alkylaryl dichlorophosphates, alkylaryl dichlorophosphonates, and alkylaryl dichlorophosphites. Exemplary organophosphorous compounds include ethyl dichlorophosphate, ethyl dichlorophosphonate, hexyl dichlorophosphate and hexyl dichlorophosphonate, for example.
The prepolymer can be formed using a variety of catalysts, including stannous catalysts and/or zinc catalysts, for example. Appropriate acid scavengers include the tertiary amines, such as triethylamine, and substituted aminopyridines, such as 4-dimethylaminopyridine, although other acid scavengers available to the skilled person can be employed according to the teachings contained herein, such as N,N,N-triethylamine, N,N-dimethyl-n-phenyl amine; N-methylmorpholine, pyridine, triethylenediamine, POLYDMAP (poly 4-dimethylaminopyridine), and REILLEX 402. In many instances, the substituted aminopyridines, such as DMAP, cause larger molecular weight polymers to form. See Holfe et al., Angew. Chem. Int. Ed. Engl. 17: 569 (1978); Scriven, Chem. Soc. Rev. 12:129 (1983). Phosphopolymers and phosphopolymer preparations obtainable from these methodologies also are provided.
In accordance with another aspect of the invention, there are provided methods of producing phosphopolymers, comprising reacting a prepolymer (as described above), preferably dissolved in an appropriate solvent, with an organophosphorous compound (as described above) in the presence of at least one acid scavenger (as described above) at a cold temperature, preferably until substantially all of the organophosphorous compound has bound with the prepolymer to form a phosphopolymer; stopping/quenching the reaction; contacting the phosphopolymer with at least one ion exchange resin, which purifies the phosphopolymer; and removing the ion exchange resin, which can be done via filtration. The reaction can be stopped/quenched with an alcohol. The acidic ion exchange resins and basic ion exchange resins can be contacted with the phosphopolymer. An acidic resin exchanges cations, and a basic resin exchanges anions. Resins can be considered strong or weak, as is known in the field. Appropriate resins include Dowex MR3, MR3C, HCR-S, M-43, DR-2030, MSC-1, Monosphere 66 and 77; Marathon C; 50WX4; Rohm and Haas Amberlyst 15 and A21; and Mitsubishi Diaion WA30. Other resins available to the skilled person can be employed in accordance with the teachings contained herein. The methods can further comprise concentrating the phosphopolymer; precipitating the phosphopolymer; and drying the phosphopolymer.
The prepolymer can be formed from one or more monomers selected from the group consisting of D,L-lactide, trimethylene carbonate, L-lactide, caproloactone, dioxanone, propylene glycol, ethylene glycol, 1,6 hexanediol, glycolide, 1,4-cyclohexane dimethanol, terephthaloyl chloride and bis(hydroxyethyl) terephthalate, for example, and the organophosphorous compound can be selected from the group consisting of alkyl dichlorophosphates, alkyl dichlorophosphonates, alkyl dichlorophosphites, aryl dichlorophosphates, aryl dichlorophosphonates, aryl dichlorophosphites, alkylaryl dichlorophosphates, alkylaryl dichlorophosphonates, and alkylaryl dichlorophosphites, for example. Exemplary organophosphorous compounds include ethyl dichlorophosphate, ethyl dichlorophosphonate, hexyl dichlorophosphate and hexyl dichlorophosphonate. The prepolymner can be formed using a stannous catalysts and/or zinc catalysts, for example.
Appropriate acid scavengers include tertiary amines, such as triethylamine, and substituted aminopyridines, such as 4-dimethylaminopyridine, although other acid scavengers available to the skilled person can be employed according to the teachings contained herein. Phosphopolymers and phosphopolymer preparations obtainable from these methodologies also are provided.
In accordance with still another aspect of the invention, there are provided methods of producing a polyphosphoesters comprising (1) reacting at least one type of diol with at least one type of organophosphorus compound in the presence of at least one acid scavenger until substantially all of the organophosphorus compound has bound with the diol to form a polyphosphoester and (2) purifying the polyphosphoester. The diol can be a straight-chain aliphatic diol, a branched aliphatic diol, a cycloaliphatic diol, an aryl, and can be monomeric or polymeric. Illustrative diols include cyclohexane dimethanol, ethylene glycol, 1,4-benzenedimethanol, 1,6 hexane diol, bis(hydroxyethyl terephthalate) and propylene glycol. Polyethylene glycols of various molecular weights, e.g., about 200 Da, about 500 Da, about 5000 Da or larger also can be employed according to the invention, and such polyethylene glycols are readily obtained by the skilled person. The diol can substitute for or be in addition to a prepolymer. Preferably, the diol is present in stoiciometric amounts to the organophosphate.
Appropriate acid scavengers include tertiary amines, such as triethylamine, and substituted aminopyridines, such as 4-dimethylaminopyridine, although other acid scavengers available to the skilled person can be employed according to the teachings contained herein. Phosphopolymers and phosphopolymer preparations obtainable from these methodologies also are provided.
In accordance with still another aspect of the invention, there are provided methods of producing polyphosphoesters, comprising: reacting a prepolymer with an organophosphorous compound in the presence of at least one acid scavenger at a cold temperature until substantially all of the organophosphorous compound has bound with the prepolymer to form a polyphosphoester; stopping the reaction; contacting the polyphosphoester with an acidic ion exchange resin and a basic ion exchange resin; and removing the acidic and basic ion exchange resins to yield a purified polyphosphester that has a reduced level of metal contaminants, such as tin and zinc. Polyphosphoesters and polyphosphoester preparations obtainable by these methods also are provided.
These and other aspects of the invention will become apparent in view of the teachings, examples and data contained herein.
Purification Methodologies
One aspect of the present invention advantageously employs ion exchange resins (xe2x80x9cIERsxe2x80x9d) to remove ionized and/or or ionizable contaminants from any polymer process stream, and is particularly useful for polymers to be used in pharmaceutical, medical device, and food product settings. Preferably, at least 50% of the contaminants are removed, more preferably at least 70% of the contaminants are removed, and still more preferably at least 90% of the contaminants are removed. For example, in the case of metal contaminants, the metal concentration following purification is 20 ppm or lower, preferably 10 ppm or lower, and still more preferably 5 ppm or lower.
Typically, at a given stage of a process stream, a polymer product is in the form of a solute. Alternatively, a solid polymer preparation can be solubilized in an appropriate solvent. Whatever the approach, post-polymerization polymers are contaminated with process byproducts. In order to remove these contaminants, at an appropriate stage of the process, the polymer solute is contacted with one or more IERs to remove the contaminants. The polymer solute/IER mixture is usually agitated in order to facilitate contact between the solution and the IER, which maximizes contaminant removal. Exemplary approaches for agitation include mechanical shaking or spinning a vessel containing the polymer solute/IER mixture, or internal stirring using a paddle, blade or stir bar. The IER treatment can be from minutes to days, preferably ranging about 2 to about 24 hours, and preferably is performed at ambient temperature or below, depending upon the polymer and the solvent. Exemplary temperatures include xe2x88x9278xc2x0 C. to 30xc2x0 C., preferably within about xe2x88x9210xc2x0 C. to 25xc2x0 C., and more preferably within about xe2x88x925xc2x0 C. to 20xc2x0 C., although any temperature within or about the above intervals are appropriate for use according to the invention. After an appropriate contact period, the IER is removed, typically through filtration and/or sedimentation.
Typical contaminants include cationic and anionic species that exist in solution. Cationic contaminants include:
(1) Alkali metals, for example lithium and sodium;
(2) Alkali earth metals, for example magnesium and calcium;
(3) Transition metals, for example iron, nickel and zinc;
(4) Other main group metals, for example aluminum and tin;
(5) Heavy metals, for example lead, cadmium and mercury; and
(6) Ammonium cations and organic cationic species, for example amines like protonated organic amines.
Other types of cationic species include electrically neutral species like organic amines that can react with strong acid IERs in protonated form to form cationic species, for example amine hydrochloride. Thus, any cationic contaminant or neutral contaminant that can be protonated to form a cationic species can be removed with ER. In the context of polymers for pharmaceutical and other medical uses, the need to remove tin and zinc is typical because these metal contaminants come from commonly used catalysts.
Anionic contaminants include:
(1) Halides, for example chlorides and bromides;
(2) Monoatomic main-group anions, for example sulfide and selenide;
(3) Polyatomic anions, for example nitrate, sulfate and phosphate; and
(4) Other organic anions, for example carboxylates, organonitrates and organophosphates.
Finally, electrically neutral species, like inorganic acids (for example, hydrochloric acid and nitric acid), can react with base IERs to form water and anionic species, which in turn can be removed by the IERs.
Solvents, including mixtures thereof, that can be used to dissolve the polymers include:
(1) Water;
(2) Alcohols, for example methanol and ethanol;
(3) Ketones, for example acetone and 2-butanone;
(4) Ethers, for example diethyl ether and tetrahydrofuran;
(5) Esters, for example ethyl acetate;
(6) Halogenated hydrocarbons, for example carbon tetrachloride, chloroform, dichloromethane, 1,2 dichloroethane and methylene chloride;
(7) Hydrocarbons, for example toluene, benzene and hexane; and
(8) Other organics, for example dimethlylsulfoxide.
The IERs to be employed must be compatible with the polymer and the solvent in which the polymer is dissolved. Preferably, the IER is wetted with the same solvent, or compatible solvent(s), used to dissolve the polymer. Appropriate resins to be used according to the invention include:
(1) Dowex MR3 and MR3C (mixed ion exchange resins containing Marathon A (strong base) and Marathon C (strong acid) resins);
(2) Dowex HCR-S (strong acidxe2x80x94styrene-DVB, gel matrix with a sulfonic acid functional group);
(3) Dowex M-43 (weak base resin (tertiary amine) made from macroporous styrenic plastic beads);
(4) Dowex DR-2030 (strong acid resinxe2x80x94styrenic plastic bead fuinctionalized with sulfonic acid groups, often referred to as a catalyst);
(5) Dowex MSC-1 (Strong acid resin);
(6) Dowex Monosphere 66 and 77 (basic resins);
(7) Marathon C (strong acid);
(8) Marathon A (strong base);
(9) 50WX4 (Strong acid);
(10) Rohm and Haas Amberlyst 15 (Acidic resin);
(11) Rohm and Haas Amberlyst A21 (Basic resin); and
(12) Mitsubishi Diaion WA30 (Basic resin).
The above listing is exemplary, and thus is not exhaustive. Other resins available to the skilled person can be employed according to the teachings contained herein.
At least one ion exchange resin is employed according to one aspect of the invention. Preferably, more than one ion exchange resin is employed, for example a strong acid resin and a weak basic resin are used to remove contaminants from a polymer.
The usefulness of IERs is demonstrated by the following, non-limiting, examples.